The regulation of sympathetic nerve activity in the chronic heart failure (CHF) state is a complex and critically important issue. Over the past 20 years this laboratory has been investigating mechanisms of abnormal neuro-humoral control of cardiovascular function in animal models of CHF. We have clearly shown that enhanced sympathetic outflow, which is characteristic of the CHF state, is a multi-factorial process involving alterations in both buffer reflexes and in the central modulation of sympathetic outflow. Exercise conditioning has been shown to reduce many of the symptoms of the CHF state. The mechanisms by which exercise conditioning is beneficial in the CHF state are largely unknown. Preliminary evidence from this laboratory suggests that exercise conditioning in CHF can not only reverse the sympatho-excitatory state but can up regulate nNOS mRNA and protein in the brain. Because nitric oxide has been shown to be a modulator of sympathetic function we hypothesize that one mechanism by which exercise conditioning reduces sympathetic outflow in CHF is by a central up regulation of nNOS in areas of the central nervous system which are critically involved in the regulation of sympathetic outflow. Therefore, we will determine the role of exercise conditioning on resting renal sympathetic nerve activity (RSNA) and on baroreflex control of RSNA as well as determining the effects of exercise conditioning on the central expression of nNOS and mRNA and protein in conscious, chronically instrumented rabbits with and without pacing-induced CHF. In addition, exercise may reduce the role of central angiotensin II on sympathetic outflow. Therefore, an additional aim of this proposal is to determine the role of central angiotensin II and its interaction with nitric oxide in rabbits with CHF. These studies will provide new and unique information on the role of exercise in the regulation of sympathetic outflow in the CHF state.